We will explore the role of adenosine, a potent coronary vasodilator, in the metabolic regulation of coronary flow. We have demonstrated that significant amounts of adenosine are released from canine hearts during reactive hyperemia and from human hearts during angina and lactate production induced by rapid atrial pacing. With assay techniques which require much smaller blood samples, we will now be able to define, in man and dogs, the temporal relationships between the onset of angina, production of adenosine, release of lactate and changes in coronary blood flow. In dogs, we will also sample blood from segmental veins draining small areas of acutely ischemic myocardium. Our purpose is to determine whether adenosine release is related to changes in coronary flow, and whether it is an isolated phenomenon or is accompanied by leakage of inorganic phosphate and creatine, suggesting concomitant uncoupling of oxidative phosphorylation, or of cytoplasmic enzymes, reflecting increased cell permeability. The usefulness of adenosine as an index of fixed regional ischemia will be determined by sampling coronary sinus blood from patients with preinfarctional angina or acute myocardial infarction. We will also determine the effects of dipyridamole and nitroglycerine on the release of adenosine in man, and whether maximum exercise causes release of adenosine from hearts with normal coronary arteries.